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Defining nephrotic syndrome from an integrative genomics perspective

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Abstract

Nephrotic syndrome (NS) is a clinical condition with a high degree of morbidity and mortality, caused by failure of the glomerular filtration barrier, resulting in massive proteinuria. Our current diagnostic, prognostic and therapeutic decisions in NS are largely based upon clinical or histological patterns such as “focal segmental glomerulosclerosis” or “steroid sensitive”. Yet these descriptive classifications lack the precision to explain the physiologic origins and clinical heterogeneity observed in this syndrome. A more precise definition of NS is required to identify mechanisms of disease and capture various clinical trajectories. An integrative genomics approach to NS applies bioinformatics and computational methods to comprehensive experimental, molecular and clinical data for holistic disease definition. A unique aspect is analysis of data together to discover NS-associated molecules, pathways, and networks. Integrating multidimensional datasets from the outset highlights how molecular lesions impact the entire individual. Data sets integrated range from genetic variation to gene expression, to histologic changes, to progression of chronic kidney disease (CKD). This review will introduce the tenets of integrative genomics and suggest how it can increase our understanding of NS from molecular and pathophysiological perspectives. A diverse group of genome-scale experiments are presented that have sought to define molecular signatures of NS. Finally, the Nephrotic Syndrome Study Network (NEPTUNE) will be introduced as an international, prospective cohort study of patients with NS that utilizes an integrated systems genomics approach from the outset. A major NEPTUNE goal is to achieve comprehensive disease definition from a genomics perspective and identify shared molecular drivers of disease.

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References

  1. (1981) The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 98:561–564

  2. Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood. Lancet 362:629–639

    Article  PubMed  Google Scholar 

  3. Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan JD, Wigfall D, Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum LA (2009) Management of childhood onset nephrotic syndrome. Pediatrics 124:747–757

    Article  PubMed  Google Scholar 

  4. Greenbaum LA, Benndorf R, Smoyer WE (2012) Childhood nephrotic syndrome–current and future therapies. Nat Rev Nephrol 8:445–458

    Article  CAS  PubMed  Google Scholar 

  5. Kiffel J, Rahimzada Y, Trachtman H (2011) Focal segmental glomerulosclerosis and chronic kidney disease in pediatric patients. Adv Chronic Kidney Dis 18:332–338

    Article  PubMed Central  PubMed  Google Scholar 

  6. Hildebrandt F (2010) Genetic kidney diseases. Lancet 375:1287–1295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. McCarthy ET, Sharma M, Savin VJ (2010) Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 5:2115–2121

    Article  PubMed  Google Scholar 

  8. Ronco P, Debiec H (2012) Pathogenesis of membranous nephropathy: recent advances and future challenges. Nat Rev Nephrol 8:203–213

    Article  CAS  PubMed  Google Scholar 

  9. Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM (2001) Delineation of prognostic biomarkers in prostate cancer. Nature 412:822–826

    Article  CAS  PubMed  Google Scholar 

  10. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  CAS  PubMed  Google Scholar 

  11. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    Article  CAS  PubMed  Google Scholar 

  12. Decock A, Ongenaert M, Hoebeeck J, De Preter K, Van Peer G, Van Criekinge W, Ladenstein R, Schulte JH, Noguera R, Stallings RL, Van Damme A, Laureys G, Vermeulen J, Van Maerken T, Speleman F, Vandesompele J (2012) Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers. Genome Biol 13:R95

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Benoit G, Machuca E, Antignac C (2010) Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 25:1621–1632

    Article  PubMed Central  PubMed  Google Scholar 

  14. Pollak MR, Genovese G, Friedman DJ (2012) APOL1 and kidney disease. Curr Opin Nephrol Hypertens 21:179–182

    Article  CAS  PubMed  Google Scholar 

  15. Greene CS, Troyanskaya OG (2010) Integrative systems biology for data-driven knowledge discovery. Semin Nephrol 30:443–454

    Article  PubMed  Google Scholar 

  16. Hawkins RD, Hon GC, Ren B (2010) Next-generation genomics: an integrative approach. Nat Rev Genet 11:476–486

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y, Mazloom AR, Chen EY, D’Agati V, Xiong H, Ross MJ, Chen N, Ma’ayan A, He JC (2012) A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med 18:580–588

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Martini S, Nair V, Patel SR, Eichinger F, Nelson RG, Weil EJ, Pezzolesi MG, Krolewski AS, Randolph A, Keller BJ, Werner T, Kretzler M (2013) From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy. Diabetes 62:2605–2612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Keller BJ, Martini S, Sedor JR, Kretzler M (2012) A systems view of genetics in chronic kidney disease. Kidney Int 81:14–21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Mardis ER (2010) The $1,000 genome, the $100,000 analysis? Genome Med 2:84

    Article  PubMed Central  PubMed  Google Scholar 

  21. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Tory K, Menyhard DK, Woerner S, Nevo F, Gribouval O, Kerti A, Stráner P, Arrondel C, Cong EH, Tulassay T, Mollet G, Perczel A, Antignac C (2014) Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 46:299–304

    Article  CAS  PubMed  Google Scholar 

  23. Kurina LM, Weiss LA, Graves SW, Parry R, Williams GH, Abney M, Ober C (2005) Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women. J Clin Endocrinol Metab 90:4747–4752

    Article  CAS  PubMed  Google Scholar 

  24. Wheeler HE, Metter EJ, Tanaka T, Absher D, Higgins J, Zahn JM, Wilhelmy J, Davis RW, Singleton A, Myers RM, Ferrucci L, Kim SK (2009) Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging. PLoS Genet 5:e1000685

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Kainz A, Wilflingseder J, Mitterbauer C, Haller M, Burghuber C, Perco P, Langer RM, Heinze G, Oberbauer R (2010) Steroid pretreatment of organ donors to prevent postischemic renal allograft failure: a randomized, controlled trial. Ann Intern Med 153:222–230

    Article  PubMed  Google Scholar 

  26. Liang Y, Kelemen A (2008) Bayesian models and meta analysis for multiple tissue gene expression data following corticosteroid administration. BMC Bioinforma 9:354

    Article  CAS  Google Scholar 

  27. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100:9440–9445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Cantor RM, Lange K, Sinsheimer JS (2010) Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 86:6–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Mechanic LE, Chen HS, Amos CI, Chatterjee N, Cox NJ, Divi RL, Fan R, Harris EL, Jacobs K, Kraft P, Leal SM, McAllister K, Moore JH, Paltoo DN, Province MA, Ramos EM, Ritchie MD, Roeder K, Schaid DJ, Stephens M, Thomas DC, Weinberg CR, Witte JS, Zhang S, Zöllner S, Feuer EJ, Gillanders EM (2012) Next generation analytic tools for large scale genetic epidemiology studies of complex diseases. Genet Epidemiol 36:22–35

    Article  PubMed Central  PubMed  Google Scholar 

  30. Awwad HM, Kirsch SH, Geisel J, Obeid R (2014) Measurement of concentrations of whole blood levels of choline, betaine, and dimethylglycine and their relations to plasma levels. J Chromatogr B Anal Technol Biomed Life Sci 957:41–45

    Article  CAS  Google Scholar 

  31. Balasz-Chmielewska I, Benetti E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, Davitaia T, Wasilewska A, Drozdz D, Szczepanska M, Jankauskiene A, Higuita LM, Ardissino G, Ozkaya O, Kuzma-Mroczkowska E, Soylemezoglu O, Ranchin B, Medynska A, Tkaczyk M, Peco-Antic A, Akil I, Jarmolinski T, Firszt-Adamczyk A, Dusek J, Simonetti GD, Gok F, Gheissari A, Emma F, Krmar RT, Fischbach M, Printza N, Simkova E, Mele C, Ghiggeri GM, Schaefer F, PodoNet Consortium (2013) Genetic screening in adolescents with steroid-resistant nephrotic syndrome. Kidney Int 84:206–213

    Article  PubMed  CAS  Google Scholar 

  32. Rood IM, Deegens JK, Wetzels JF (2012) Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Nephrol Dial Transplant 27:882–890

    Article  CAS  PubMed  Google Scholar 

  33. Saleem MA (2013) New developments in steroid-resistant nephrotic syndrome. Pediatr Nephrol 28:699–709

    Article  PubMed  Google Scholar 

  34. McCarthy HJ, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJ, Christian M, Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA, RADAR the UK SRNS Study Group (2013) Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 8:637–648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Machuca E, Hummel A, Nevo F, Dantal J, Martinez F, Al-Sabban E, Baudouin V, Abel L, Grünfeld JP, Antignac C (2009) Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney Int 75:727–735

    Article  CAS  PubMed  Google Scholar 

  36. Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, Gasser DL (2008) Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet 4:e1000061

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Gasser DL, Winkler CA, Peng M, An P, McKenzie LM, Kirk GD, Shi Y, Xie LX, Marbois BN, Clarke CF, Kopp JB (2013) Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10. Am J Physiol Ren Physiol 305:F1228–F1238

    Article  CAS  Google Scholar 

  38. Divers J, Palmer ND, Lu L, Langefeld CD, Rocco MV, Hicks PJ, Murea M, Ma L, Bowden DW, Freedman BI (2013) Gene-gene interactions in APOL1-associated nephropathy. Nephrol Dial Transplant 29:587–594

    Article  PubMed  CAS  Google Scholar 

  39. Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, Sanna-Cherchi S, Men CJ, Julian BA, Wyatt RJ, Novak J, He JC, Wang H, Lv J, Zhu L, Wang W, Wang Z, Yasuno K, Gunel M, Mane S, Umlauf S, Tikhonova I, Beerman I, Savoldi S, Magistroni R, Ghiggeri GM, Bodria M, Lugani F, Ravani P, Ponticelli C, Allegri L, Boscutti G, Frasca G, Amore A, Peruzzi L, Coppo R, Izzi C, Viola BF, Prati E, Salvadori M, Mignani R, Gesualdo L, Bertinetto F, Mesiano P, Amoroso A, Scolari F, Chen N, Zhang H, Lifton RP (2011) Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43:321–327

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq-Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R (2011) Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med 364:616–626

    Article  CAS  PubMed  Google Scholar 

  41. Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M, Maeda S, Nakamura Y, Noiri E (2011) Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43:459–463

    Article  CAS  PubMed  Google Scholar 

  42. Gu HF, Brismar K (2012) Genetic association studies in diabetic nephropathy. Curr Diabetes Rev 8:336–344

    Article  CAS  PubMed  Google Scholar 

  43. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175–1184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Keller B, Martini S, Sedor J, Kretzler M (2010) Linking variants from genome-wide association analysis to function via transcriptional network analysis. Semin Nephrol 30:177–184

    Article  PubMed Central  PubMed  Google Scholar 

  46. He JC, Chuang PY, Ma’ayan A, Iyengar R (2012) Systems biology of kidney diseases. Kidney Int 81:22–39

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Cohen CD, Frach K, Schlondorff D, Kretzler M (2002) Quantitative gene expression analysis in renal biopsies: a novel protocol for a high-throughput multicenter application. Kidney Int 61:133–140

    Article  CAS  PubMed  Google Scholar 

  49. Yasuda Y, Cohen CD, Henger A, Kretzler M (2006) Gene expression profiling analysis in nephrology: towards molecular definition of renal disease. Clin Exp Nephrol 10:91–98

    Article  CAS  PubMed  Google Scholar 

  50. Saleem MA, O’Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, Xing CY, Ni L, Mathieson PW, Mundel P (2002) A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 13:630–638

    CAS  PubMed  Google Scholar 

  51. Sarrab RM, Lennon R, Ni L, Wherlock MD, Welsh GI, Saleem MA (2011) Establishment of conditionally immortalised human glomerular mesangial cells in culture, with unique migratory properties. Am J Physiol Ren Physiol 301:F1131–F1138

    Article  CAS  Google Scholar 

  52. Satchell SC, Tasman CH, Singh A, Ni L, Geelen J, von Ruhland CJ, O’Hare MJ, Saleem MA, van den Heuvel LP, Mathieson PW (2006) Conditionally immortalized human glomerular endothelial cells expressing fenestrations in response to VEGF. Kidney Int 69:1633–1640

    Article  CAS  PubMed  Google Scholar 

  53. Boerries M, Grahammer F, Eiselein S, Buck M, Meyer C, Goedel M, Bechtel W, Zschiedrich S, Pfeifer D, Laloë D, Arrondel C, Gonçalves S, Krüger M, Harvey SJ, Busch H, Dengjel J, Huber TB (2013) Molecular fingerprinting of the podocyte reveals novel gene and protein regulatory networks. Kidney Int 83:1052–1064

    Article  CAS  PubMed  Google Scholar 

  54. Brunskill EW, Georgas K, Rumballe B, Little MH, Potter SS (2011) Defining the molecular character of the developing and adult kidney podocyte. PLoS One 6:e24640

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Lindenmeyer MT, Eichinger F, Sen K, Anders HJ, Edenhofer I, Mattinzoli D, Kretzler M, Rastaldi MP, Cohen CD (2010) Systematic analysis of a novel human renal glomerulus-enriched gene expression dataset. PLoS One 5:e11545

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Cuellar LM, Fujinaka H, Yamamoto K, Miyamoto M, Tasaki M, Zhao L, Tamer I, Yaoita E, Yoshida Y, Yamamoto T (2009) Identification and localization of novel genes preferentially expressed in human kidney glomerulus. Nephrology 14:94–104

    Article  CAS  PubMed  Google Scholar 

  57. Ju W, Greene CS, Eichinger F, Nair V, Hodgin JB, Bitzer M, Lee YS, Zhu Q, Kehata M, Li M, Jiang S, Rastaldi MP, Cohen CD, Troyanskaya OG, Kretzler M (2013) Defining cell-type specificity at the transcriptional level in human disease. Genome Res 23:1862–1873

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Nishibori Y, Katayama K, Parikka M, Oddsson A, Nukui M, Hultenby K, Wernerson A, He B, Ebarasi L, Raschperger E, Norlin J, Uhlén M, Patrakka J, Betsholtz C, Tryggvason K (2011) Glcci1 deficiency leads to proteinuria. J Am Soc Nephrol 22:2037–2046

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Hodgin JB, Borczuk AC, Nasr SH, Markowitz GS, Nair V, Martini S, Eichinger F, Vining C, Berthier CC, Kretzler M, D’Agati VD (2010) A molecular profile of focal segmental glomerulosclerosis from formalin-fixed, paraffin-embedded tissue. Am J Pathol 177:1674–1686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Reich HN, Tritchler D, Cattran DC, Herzenberg AM, Eichinger F, Boucherot A, Henger A, Berthier CC, Nair V, Cohen CD, Scholey JW, Kretzler M (2010) A molecular signature of proteinuria in glomerulonephritis. PLoS One 5:e13451

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  61. Ju W, Eichinger F, Bitzer M, Oh J, McWeeney S, Berthier CC, Shedden K, Cohen CD, Henger A, Krick S, Kopp JB, Stoeckert CJ Jr, Dikman S, Schröppel B, Thomas DB, Schlondorff D, Kretzler M, Böttinger EP (2009) Renal gene and protein expression signatures for prediction of kidney disease progression. Am J Pathol 174:2073–2085

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Schmid H, Henger A, Cohen CD, Frach K, Gröne HJ, Schlöndorff D, Kretzler M (2003) Gene expression profiles of podocyte-associated molecules as diagnostic markers in acquired proteinuric diseases. J Am Soc Nephrol 14:2958–2966

    Article  CAS  PubMed  Google Scholar 

  63. Fukuda A, Wickman LT, Venkatareddy MP, Wang SQ, Chowdhury MA, Wiggins JE, Shedden KA, Wiggins RC (2012) Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker. Nephrol Dial Transplant 27:4079–4087

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Wickman L, Afshinnia F, Wang SQ, Yang Y, Wang F, Chowdhury M, Graham D, Hawkins J, Nishizono R, Tanzer M, Wiggins J, Escobar GA, Rovin B, Song P, Gipson D, Kershaw D, Wiggins RC (2013) Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases. J Am Soc Nephrol 24:2081–2095

    Article  CAS  PubMed  Google Scholar 

  65. Ling XB, Sigdel TK, Lau K, Ying L, Lau I, Schilling J, Sarwal MM (2010) Integrative urinary peptidomics in renal transplantation identifies biomarkers for acute rejection. J Am Soc Nephrol 21:646–653

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Jiang H, Guan G, Zhang R, Liu G, Cheng J, Hou X, Cui Y (2009) Identification of urinary soluble E-cadherin as a novel biomarker for diabetic nephropathy. Diabetes Metab Res Rev 25:232–241

    Article  CAS  PubMed  Google Scholar 

  67. Knepper MA, Pisitkun T (2007) Exosomes in urine: who would have thought…? Kidney Int 72:1043–1045

    Article  CAS  PubMed  Google Scholar 

  68. Gonzales PA, Pisitkun T, Hoffert JD, Tchapyjnikov D, Star RA, Kleta R, Wang NS, Knepper MA (2009) Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol 20:363–379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Woroniecki RP, Orlova TN, Mendelev N, Shatat IF, Hailpern SM, Kaskel FJ, Goligorsky MS, O’Riordan E (2006) Urinary proteome of steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome of childhood. Am J Nephrol 26:258–267

    Article  CAS  PubMed  Google Scholar 

  70. Khurana M, Traum AZ, Aivado M, Wells MP, Guerrero M, Grall F, Libermann TA, Schachter AD (2006) Urine proteomic profiling of pediatric nephrotic syndrome. Pediatr Nephrol 21:1257–1265

    Article  PubMed Central  PubMed  Google Scholar 

  71. Reinhardt CP, Germain MJ, Groman EV, Mulhern JG, Kumar R, Vaccaro DE (2008) Functional immunoassay technology (FIT), a new approach for measuring physiological functions: application of FIT to measure glomerular filtration rate (GFR). Am J Physiol Ren Physiol 295:F1583–F1588

    Article  CAS  Google Scholar 

  72. Good DM, Zurbig P, Argiles A, Bauer HW, Behrens G, Coon JJ, Dakna M, Decramer S, Delles C, Dominiczak AF, Ehrich JH, Eitner F, Fliser D, Frommberger M, Ganser A, Girolami MA, Golovko I, Gwinner W, Haubitz M, Herget-Rosenthal S, Jankowski J, Jahn H, Jerums G, Julian BA, Kellmann M, Kliem V, Kolch W, Krolewski AS, Luppi M, Massy Z, Melter M, Neusüss C, Novak J, Peter K, Rossing K, Rupprecht H, Schanstra JP, Schiffer E, Stolzenburg JU, Tarnow L, Theodorescu D, Thongboonkerd V, Vanholder R, Weissinger EM, Mischak H, Schmitt-Kopplin P (2010) Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease. Mol Cell Proteomics 9:2424–2437

    Article  PubMed Central  PubMed  Google Scholar 

  73. Vivekanandan-Giri A, Slocum JL, Buller CL, Basrur V, Ju W, Pop-Busui R, Lubman DM, Kretzler M, Pennathur S (2011) Urine glycoprotein profile reveals novel markers for chronic kidney disease. Int J Proteomics 2011:214715

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Hogan MC, Johnson KL, Zenka RM, Cristine Charlesworth M, Madden BJ, Mahoney DW, Oberg AL, Huang BQ, Leontovich AA, Nesbitt LL, Bakeberg JL, McCormick DJ, Robert Bergen H, Ward CJ (2013) Subfractionation, characterization, and in-depth proteomic analysis of glomerular membrane vesicles in human urine. Kidney Int 85:1225–1237

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Zhou H, Kajiyama H, Tsuji T, Hu X, Leelahavanichkul A, Vento S, Frank R, Kopp JB, Trachtman H, Star RA, Yuen PS (2013) Urinary exosomal Wilms’ tumor-1 as a potential biomarker for podocyte injury. Am J Physiol Ren Physiol 305:F553–F559

    Article  CAS  Google Scholar 

  76. Mohtat D, Susztak K (2010) Fine tuning gene expression: the epigenome. Semin Nephrol 30:468–476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Thiagarajan RD, Cloonan N, Gardiner BB, Mercer TR, Kolle G, Nourbakhsh E, Wani S, Tang D, Krishnan K, Georgas KM, Rumballe BA, Chiu HS, Steen JA, Mattick JS, Little MH, Grimmond SM (2011) Refining transcriptional programs in kidney development by integration of deep RNA-sequencing and array-based spatial profiling. BMC Genomics 12:441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Woroniecki R, Gaikwad AB, Susztak K (2011) Fetal environment, epigenetics, and pediatric renal disease. Pediatr Nephrol 26:705–711

    Article  PubMed Central  PubMed  Google Scholar 

  79. Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfe BD, McManus MT, Benzing T, Miner JH (2008) Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease. J Am Soc Nephrol 19:2150–2158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Shi S, Yu L, Chiu C, Sun Y, Chen J, Khitrov G, Merkenschlager M, Holzman LB, Zhang W, Mundel P, Bottinger EP (2008) Podocyte-selective deletion of dicer induces proteinuria and glomerulosclerosis. J Am Soc Nephrol 19:2159–2169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Zhdanova O, Srivastava S, Di L, Li Z, Tchelebi L, Dworkin S, Johnstone DB, Zavadil J, Chong MM, Littman DR, Holzman LB, Barisoni L, Skolnik EY (2011) The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy. Kidney Int 80:719–730

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Ho J, Ng KH, Rosen S, Dostal A, Gregory RI, Kreidberg JA (2008) Podocyte-specific loss of functional microRNAs leads to rapid glomerular and tubular injury. J Am Soc Nephrol 19:2069–2075

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Luo Y, Wang C, Chen X, Zhong T, Cai X, Chen S, Shi Y, Hu J, Guan X, Xia Z, Wang J, Zen K, Zhang CY, Zhang C (2013) Increased serum and urinary MicroRNAs in children with idiopathic nephrotic syndrome. Clin Chem 59:658–666

    Article  CAS  PubMed  Google Scholar 

  84. Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, Tauber S, Bilban M, Wang S, Kain R, Böhmig GA, Moeller MJ, Gröne HJ, Englert C, Martinez J, Kerjaschki D (2013) Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Nat Med 19:481–487

    Article  CAS  PubMed  Google Scholar 

  85. Smyth LJ, McKay GJ, Maxwell AP, McKnight AJ (2013) DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease. Epigenetics 9:366–376

    Article  PubMed  CAS  Google Scholar 

  86. Ko YA, Mohtat D, Suzuki M, Park AS, Izquierdo MC, Han SY, Kang HM, Si H, Hostetter T, Pullman JM, Fazzari M, Verma A, Zheng D, Greally JM, Susztak K (2013) Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol 14:R108

    Article  PubMed Central  PubMed  Google Scholar 

  87. Grimm PC, Nickerson P, Gough J, McKenna R, Jeffery J, Birk P, Rush DN (1999) Quantitation of allograft fibrosis and chronic allograft nephropathy. Pediatr Transplant 3:257–270

    Article  CAS  PubMed  Google Scholar 

  88. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, Feehally J, Roberts IS, Troyanov S, Alpers CE, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D’Agati V, D’Amico G, Emancipator S, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo A, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hogg RJ, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Leung CB, Li LS, Li PK, Liu ZH, Mackinnon B, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H (2009) The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 76:534–545

    Article  PubMed  Google Scholar 

  89. Maluf DG, Mas VR, Archer KJ, Yanek K, Gibney EM, King AL, Cotterell A, Fisher RA, Posner MP (2008) Molecular pathways involved in loss of kidney graft function with tubular atrophy and interstitial fibrosis. Mol Med 14:276–285

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Henger A, Kretzler M, Doran P, Bonrouhi M, Schmid H, Kiss E, Cohen CD, Madden S, Porubsky S, Gröne EF, Schlöndorff D, Nelson PJ, Gröne HJ (2004) Gene expression fingerprints in human tubulointerstitial inflammation and fibrosis as prognostic markers of disease progression. Kidney Int 65:904–917

    Article  CAS  PubMed  Google Scholar 

  91. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC (2004) Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 43:368–382

    Article  PubMed  Google Scholar 

  92. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F, Fogo AB, Ginzler EM, Hebert L, Hill G, Hill P, Jennette JC, Kong NC, Lesavre P, Lockshin M, Looi LM, Makino H, Moura LA, Nagata M (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15:241–250

    Article  PubMed  Google Scholar 

  93. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M (2008) Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 8:753–760

    Article  CAS  PubMed  Google Scholar 

  94. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA (2011) APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 22:2129–2137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Tzur S, Rosset S, Shemer R, Yudkovsky G, Selig S, Tarekegn A, Bekele E, Bradman N, Wasser WG, Behar DM, Skorecki K (2010) Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 128:345–350

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Papeta N, Kiryluk K, Patel A, Sterken R, Kacak N, Snyder HJ, Imus PH, Mhatre AN, Lawani AK, Julian BA, Wyatt RJ, Novak J, Wyatt CM, Ross MJ, Winston JA, Klotman ME, Cohen DJ, Appel GB, D’Agati VD, Klotman PE, Gharavi AG (2011) APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. J Am Soc Nephrol 22:1991–1996

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Lee BT, Kumar V, Williams TA, Abdi R, Bernhardy A, Dyer C, Conte S, Genovese G, Ross MD, Friedman DJ, Gaston R, Milford E, Pollak MR, Chandraker A (2012) The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am J Transplant 12:1924–1928

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Reeves-Daniel AM, DePalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, Langefeld CD, Bowden DW, Hicks PJ, Stratta RJ, Lin JJ, Kiger DF, Gautreaux MD, Divers J, Freedman BI (2011) The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant 11:1025–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Bruggeman LA, O’Toole JF, Ross MD, Madhavan SM, Smurzynski M, Wu K, Bosch RJ, Gupta S, Pollak MR, Sedor JR, Kalayjian RC (2013) Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD. J Am Soc Nephrol 25:634–644

  100. Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, Feldman HI, Parekh RS, Kusek JW, Greene TH, Fink JC, Anderson AH, Choi MJ, Wright JT Jr, Lash JP, Freedman BI, Ojo A, Winkler CA, Raj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz MS, Appel LJ, AASK Study Investigators; CRIC Study Investigators (2013) APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 369:2183–2196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Madhavan SM, O’Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR (2011) APOL1 localization in normal kidney and nondiabetic kidney disease. J Am Soc Nephrol 22:2119–2128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KE, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M (2013) Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int 83:749–756

    Article  PubMed Central  PubMed  Google Scholar 

  103. Barisoni L, Nast CC, Jennette JC, Hodgin JB, Herzenberg AM, Lemley KV, Conway CM, Kopp JB, Kretzler M, Lienczewski C, Avila-Casado C, Bagnasco S, Sethi S, Tomaszewski J, Gasim AH, Hewitt SM (2013) Digital pathology evaluation in the multicenter nephrotic syndrome study network (NEPTUNE). Clin J Am Soc Nephrol 8:1449–1459

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Expert graphical contribution by Dr. Joseph Laycock is highly appreciated.

MS is supported by 1K08-DK100662-01 and the U54DK083912 Nephrotic Syndrome Study Network Consortium

JBH is supported by 1K08-DK088944-04 and the NephCure-ASN Foundation for Kidney Research

MK is supported by U54DK083912 Nephrotic Syndrome Study Network Consortium and P30 DK081943 George M. O’Brien Kidney Research Core Center at the University of Michigan

The Nephrotic Syndrome Study Network Consortium (NEPTUNE; U54-DK-083912) is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes and Digestive and Kidney Diseases

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Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, 8220D MSRB III, West Medical Center Drive, Ann Arbor, MI, 48109, USA

    Matthew G. Sampson

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Jeffrey B. Hodgin

  3. Division of Nephrology, Department of Internal Medicine and Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 1560 MSRB II, 1150W. Medical Center Dr.-SPC5676, Ann Arbor, MI, 48109-5676, USA

    Matthias Kretzler

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Correspondence to Matthew G. Sampson or Matthias Kretzler.

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Sampson, M.G., Hodgin, J.B. & Kretzler, M. Defining nephrotic syndrome from an integrative genomics perspective. Pediatr Nephrol 30, 51–63 (2015). https://doi.org/10.1007/s00467-014-2857-9

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